The evolution of extracellular vesicles: From passive transporters to active architects of microenvironmental homeostasis
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The evolution of extracellular vesicles: From passive transporters to active architects of microenvironmental homeostasis

Jingjun Zhou
1,2
,
Yuxin Xiong
1,2
,
Ruolang Pan
3
,
Jianzhong Shao
1,2
,
Ye Chen
1,2,*
*Correspondence to: Ye Chen, College of Life Sciences, and Department of Genetic and Metabolic Disease, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents’ Health and Diseases, Hangzhou 310058, Zhejiang, China; Key Laboratory of Cell and Molecular Intelligent Design and Development of Zhejiang Province, Hangzhou 310058, Zhejiang, China. E-mail: yechency@zju.edu.cn
EXO. 2026;1:202621. 10.70401/EXO.2026.0018
Received: May 29, 2026Accepted: August 12, 2026Published: August 12, 2026
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This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Once dismissed as mere cellular waste, extracellular vesicles (EVs) have undergone a conceptual redefinition, emerging as programmable therapeutic scaffolds with broad biomedical applications. Modern EV design has progressed past the conventional framework of localized cargo delivery to isolated recipient cells; instead, the focus has shifted toward systemic, multi-cellular niche remodeling aimed at restoring tissue-level homeostasis. This review provides a comprehensive analysis of the engineering strategies to overcome the biological bottlenecks of naive EVs, specifically rapid systemic clearance and inefficient cytosolic delivery. We detail current strategies for active loading and for bypassing endolysosomal entrapment to facilitate in-situ translation of therapeutic mRNA. Furthermore, we discuss how the synergy between engineered EVs and responsive biomaterial scaffolds provides the spatiotemporal control necessary for localized reprogramming of diseased microenvironments. Finally, by examining application paradigms across oncology, regenerative medicine, and neurodegeneration alongside existing regulatory classification frameworks, this review provides a roadmap for transitioning intelligent vesicle platforms from benchtop discovery to clinical-grade compliance.

Keywords

Extracellular vesicles, engineered extracellular vesicles, mRNA delivery, biomaterial-assisted delivery, in-situ translation, niche remodeling, microenvironmental homeostasis

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Zhou J, Xiong Y, Pan R, Shao J, Chen Y. The evolution of extracellular vesicles: From passive transporters to active architects of microenvironmental homeostasis. EXO. 2026;1:202621. https://doi.org/10.70401/EXO.2026.0018

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